The association between autoantibodies and risk for venous thromboembolic events among patients with rheumatoid arthritis

• Published in: Rheumatology (Oxford, England) Vol. 62; no. 6; pp. 2106 - 2112
• Main Authors: Westerlind, Helga, Kastbom, Alf, Rönnelid, Johan, Hansson, Monika, Alfredsson, Lars, Mathsson-Alm, Linda, Serre, Guy, Cornillet, Martin, Holmdahl, Rikard, Skriner, Karl, Bang, Holger, Klareskog, Lars, Saevarsdottir, Saedis, Lundberg, Karin, Grönwall, Caroline, Askling, Johan
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01-06-2023
• Subjects: antibody; Arthritis, Rheumatoid - diagnosis; Autoantibodies; Clinical Science; cohort; Fibrinogen; Humans; Immunoglobulin Isotypes; Immunoglobulin M; Medicin och hälsovetenskap; Peptides, Cyclic; Rheumatoid Factor; risk; Sweden; venous thromboembolism; Venous Thromboembolism - epidemiology; Venous Thromboembolism - etiology; Venous Thrombosis; Sweden; antibody; fibrinogen; venous thromboembolism; cohort; risk; RA
• ISSN: 1462-0324; 1462-0332; 1462-0332
• DOI: 10.1093/rheumatology/keac601

Abstract
Objectives
To assess the association between venous thromboembolic (VTE) events and autoantibodies, following patients from RA diagnosis, measuring occurrence, levels and collective load of different autoantibodies against post-translational protein modifications, in particular recognizing citrullination (e.g. citrullinated fibrinogen) and RF by isotype.
Methods
A cohort of 2814 patients with newly diagnosed RA were followed for incident VTE through register linkages. Sera from RA diagnosis were centrally analysed for antibodies to second generation cyclic citrullinated peptides (anti-CCP2), 20 anti-citrullinated protein antibody (ACPA) fine-specificities, antibodies to additional protein modifications (carbamylation and acetylation) and RF by isotype. Association between baseline serology status and future VTE was analysed using Cox regression adjusted for age, sex and calendar period of RA diagnosis, overall and stratified by anti-CCP2 and RF positivity.
Results
During a median 16 years of follow-up, 213 first-ever VTE events were registered (5.0/1000 person-years). IgG anti-CCP2 (present in 65% of cohort) associated with VTE (hazard ratio [HR] = 1.33, 95% CI: 1.00, 1.78), in a dose-response manner. The risk of VTE increased with number of ACPA fine-specificities. IgM RF, but no other RF isotypes, associated with VTE (HR = 1.38, 95% CI: 1.04, 1.82). The associations were independent from smoking and HLA-DRB1 shared epitope alleles. None of the carbamylated or acetylated antibody reactivities associated with VTE.
Conclusion
Anti-CCP2, load of ACPA fine-specificities and IgM RF at RA diagnosis are associated with an increased risk of future VTE in RA. Antibodies to citrullinated fibrinogen did not differ substantially from other ACPA fine-specificities. Autoreactivity to other post-translational modifications was not associated with VTE risk.